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1.
J Enzyme Inhib Med Chem ; 34(1): 1573-1589, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852269

RESUMO

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 µM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridazinas/síntese química , Piridazinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Bioorg Chem ; 92: 103239, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513938

RESUMO

Cyclin Dependent Kinases CDKs unpredictable activity has been accounted for a wide assortment of human malignancies, so it might be conceivable to design pharmacologically relevant ligands that go about as specific and potent inhibitors of CDK2 action. In this respect, a series of novel pyrazolo[1,5-a][1,3,5]triazine derivatives were designed, synthesized and evaluated for CDK2 enzyme inhibitory and anticancer activity. Compounds 9f and 10c showed best CDK2 inhibition among the newly synthesized compounds, with percent inhibition at 82.38%, and 81.96% against CDK2 and IC50 of 1.85 and 2.09 µM, respectively. Additionally, the newly synthesized compounds were tested for their antiproliferative activity against 60 NCI cell lines. Molecular docking revealed the binding mode of these new compounds into the roscovitine binding site of CDK2 enzyme (PDB code: 3ddq). Conclusively, pyrazolotriazine derivatives represent a talented starting point for further study as anticancer drug.

3.
Bioorg Chem ; 82: 340-359, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30428414

RESUMO

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Indazóis/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Caspase 3/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Drogas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Termodinâmica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
Bioorg Chem ; 81: 612-629, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248512

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC50 values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent.


Assuntos
Desenho de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
R Soc Open Sci ; 5(6): 172407, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30110445

RESUMO

A series of novel pyranoquinolinone-based Schiff's bases were designed and synthesized. They were evaluated for topoisomerase IIß (TOP2B) inhibitory activity, and cytotoxicity against breast cancer cell line (MCF-7) for the development of novel anticancer agents. A molecular docking study was employed to investigate their binding and functional properties as TOP2B inhibitors, using the Discovery Studio 2.5 software, where they showed very interesting ability to intercalate the DNA-topoisomerase complex. Compounds 2a, 2c and 2f showed high docking score values (82.36% -29.98 kcal mol-1 for compound 2a, 78.18% -26.98 kcal mol-1 for compound 2c and 78.65, -28.11 kcal mol-1 for compound 2f) and revealed the highest enzyme inhibition activity. The best hit compounds exhibited highly potent TOP2B inhibitors with submicromolar IC50 at 5 µM compared to the reference doxorubicin.

6.
Eur J Med Chem ; 155: 316-336, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29902719

RESUMO

In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 µM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 µM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 µM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 152: 318-328, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29734000

RESUMO

With the continued rise of antibiotic resistance and reduced susceptibility to almost all front-line antibiotics, multidrug-resistant Gram-positive bacterial infections represent an incessant threat to healthcare providers. This study presents a new series of phenylthiazole compounds where two active moieties were combined into one scaffold. The antibacterial activity of the hybrid structures extended to include several clinically-relevant multi-drug resistant pathogens including methicillin-resistant and vancomycin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, vancomycin-resistant enterococci, cephalosporin-resistant and methicillin-resistant Streptococcus pneumoniae, and Listeria monocytogenes. In addition, the most potent compounds, 16a and 17a, exhibited a fast bactericidal mode of action in vitro with low susceptibility to induce bacterial resistance. In addition to its potent spectrum of activity against Gram-positive bacterial pathogens, compound 17a was found to be metabolically stable in rats, with a half-life of 4 h.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Listeria monocytogenes/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Staphylococcus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
8.
Drug Res (Stuttg) ; 68(9): 485-498, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29433143

RESUMO

Pyrrolopyrimidine derivatives represent a class of biologically active heterocyclic compounds which can serve as promising scaffolds that display remarkable biological activities, such as anti-inflammatory, antimicrobial, antiviral and anticancer. In the last few years, several pyrrolopyrimidine derivatives have been approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Due to their inimitable antioxidant and anti-tumor properties, researchers were inspired to develop novel derivatives for the treatment of different types of cancer. The present review summarizes recent literature up to 2017 on the most recent development in the medicinal chemistry of pyrrolopyrimidine derivatives and their potential as anticancer therapeutics, especially compounds acting as kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Desenho de Drogas , Humanos , Relação Estrutura-Atividade
9.
Bioorg Chem ; 75: 368-392, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29096097

RESUMO

EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques. The optimized compounds were synthesized and subjected to EGFR binding assay and accordingly some more potent inhibitors were obtained. The most potent quinoline-3-carboxamides were the furan derivative 5o; thiophene derivative 6b; and benzyloxy derivative 10 showing EGFR IC50 values 2.61, 0.49 and 1.73 µM, respectively. Furthermore, the anticancer activity of compounds eliciting potent EGFR inhibition (5o, 5p, 6b, 8a, 8b, and 10) was evaluated against MCF-7 cell line where they exhibited IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 µM, respectively. Compound 6b was selected as lead structure for further optimization hoping to produce more potent EGFR inhibitors.


Assuntos
Amidas/química , Antineoplásicos/síntese química , Desenho de Drogas , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Quinolinas/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Quinolinas/metabolismo , Quinolinas/farmacologia , Relação Estrutura-Atividade , Termodinâmica
10.
Eur J Med Chem ; 142: 131-151, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28754471

RESUMO

Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.


Assuntos
Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Amplificação de Genes , Humanos , Modelos Moleculares , Neoplasias/genética , Neoplasias/metabolismo , Mutação Puntual , Domínios Proteicos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/química , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
11.
ChemMedChem ; 12(13): 1045-1054, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28544630

RESUMO

Herein we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric chemokine receptor 2 (CXCR2) inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2, with IC50 values less than 10 µm and selectivity over CXCR4. Our ADMET simulations suggest favorable drug-like properties for the active compounds. Importantly, we developed a predictive model that can distinguish active from inactive compounds; this will serve as a valuable tool to guide the design of optimized compounds to be evaluated in preclinical models.


Assuntos
Benzotiazóis/farmacologia , Compostos de Fenilureia/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Benzotiazóis/síntese química , Benzotiazóis/toxicidade , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/toxicidade , Receptores CXCR4/antagonistas & inibidores , Relação Estrutura-Atividade , beta-Arrestina 2/metabolismo
13.
Z Naturforsch C J Biosci ; 71(11-12): 393-402, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27508961

RESUMO

Ocimum is a genus of considerable importance in traditional medicine worldwide. The goal of this study was to examine the anti-acetylcholinesterase activity of Ocimum essential oils and to correlate the activity with their chemical profiles using a metabolome based GC-MS approach coupled to chemometrics. Further, molecular docking was adopted to rationalize the activity of some essential oil isolates. Essential oil prepared from the four species O. basilicum, O. africanum, O. americanum, and O. minimum exhibited significant anti-acetylcholinesterase activity with (IC50 0.22, 0.175, 0.57 and 0.152 mg/mL, respectively) comparable to that of physostigmine (IC50 0.27 mg/mL). The phenylpropanoids (i.e. estragole) constituted the most dominant chemical group in O. basilicum (sweet basil) and O. minimum, whereas camphor (a ketone) was the most abundant in O. africanum and O. americanum. Supervised and unsupervised multivariate data analyses clearly separated O. africanum and O. americanum from other accessions, with estragole, camphor and, to less extent, ß-linalool contributing to species segregation. Estragole was found the most active AchE inhibitor (IC50 0.337 µM) followed by cineole (IC50 2.27 µM), camphor (IC50 21.43 µM) and eugenol (IC50 40.32 µM). Molecular docking revealed that these compounds bind to key amino acids in the catalytic domain of AchE, similar to standard drugs.


Assuntos
Acetilcolinesterase/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Ocimum/química , Óleos Voláteis/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Análise Multivariada , Especificidade da Espécie
14.
Sci Rep ; 6: 24460, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27080011

RESUMO

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 µM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Furanos , Ornitina/análogos & derivados , Pirimidinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/química , Desenho de Drogas , Furanos/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Ornitina/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química
15.
ChemMedChem ; 10(11): 1915-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26350292

RESUMO

Previously, we reported the identification of a thiazolidinedione-based adenosine monophosphate activated protein kinase (AMPK) activator, compound 1 (N-[4-({3-[(1-methylcyclohexyl)methyl]-2,4-dioxothiazolidin-5-ylidene}methyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide), which provided a proof of concept to delineate the intricate role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial-mesenchymal transition (EMT) in cancer cells. In this study, we used 1 as a scaffold to conduct lead optimization, which generated a series of derivatives. Analysis of the antiproliferative and AMPK-activating activities of individual derivatives revealed a distinct structure-activity relationship and identified 59 (N-(3-nitrophenyl)-N'-{4-[(3-{[3,5-bis(trifluoromethyl)phenyl]methyl}-2,4-dioxothiazolidin-5-ylidene)methyl]phenyl}urea) as the optimal agent. Relative to 1, compound 59 exhibits multifold higher potency in upregulating AMPK phosphorylation in various cell lines irrespective of their liver kinase B1 (LKB1) functional status, accompanied by parallel changes in the phosphorylation/expression levels of p70S6K, Akt, Foxo3a, and EMT-associated markers. Consistent with its predicted activity against tumors with activated Akt status, orally administered 59 was efficacious in suppressing the growth of phosphatase and tensin homologue (PTEN)-null PC-3 xenograft tumors in nude mice. Together, these findings suggest that 59 has clinical value in therapeutic strategies for PTEN-negative cancer and warrants continued investigation in this regard.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Ativadores de Enzimas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Humanos , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Bioorg Chem ; 57: 65-82, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25233258

RESUMO

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb-f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa-g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC50 ranging from 2.27 to 10.71µM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1-11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Relação Quantitativa Estrutura-Atividade
17.
Bioorg Chem ; 54: 21-30, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24727279

RESUMO

A new series of 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid amide and 3,5,6,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4-one derivatives were designed, synthesized, their binding and functional properties as α1-adrenoreceptors blockers were evaluated. A new validated α1-adrenoreceptor blocker pharmacophore model (hypothesis) was generated using Discovery Studio 2.5. The compare-fit study for the designed molecules with the generated hypothesis was fulfilled and several compounds showed significant high fit values. Compounds IVa-c, VIIa-d, VIIIa-c, Xa-c, XIa-d have shown blocking activity ranging from 46.73% up to 94.74% compared to 99.17% for prazosin.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Desenho de Drogas , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animais , Aorta/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 61: 122-31, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23063746

RESUMO

This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 µM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase.


Assuntos
Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/farmacologia , Desenho de Drogas , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Óxidos S-Cíclicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 14(4): 898-910, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16337797

RESUMO

A series of new imidazo[5,1-b]quinazoline derivatives (VII-IX) was designed, synthesized, and biologically evaluated for their in vivo hypotensive or hypertensive activities. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to both the alpha(1)-adrenoceptor (alpha(1)-AR) agonist and alpha(1)-adrenoceptor (alpha(1)-AR) antagonist hypotheses. These hypotheses were generated from their corresponding lead compounds using CATALYST software. The simulation studies predicted that compounds IXa and IXe would have probable affinity for the alpha(1)-AR antagonist hypothesis, while compounds IXb, IXc, and IXg predicted a higher affinity for the alpha(1)-AR agonist hypothesis. In vivo biological evaluation of these compounds for their effects on the blood pressure of normotensive cats was consistent with the results of molecular modeling studies, where compounds IXa and IXe exhibited hypotensive activity, while compounds IXb, IXc, and IXg resulted in increasing the blood pressure of the experimental animals at different doses.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 1 , Desenho de Drogas , Imidazóis/química , Imidazóis/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Catálise , Gatos , Imidazóis/síntese química , Imidazóis/metabolismo , Ligantes , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Relação Estrutura-Atividade
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